OBJECTIVES: Outcomes trials are currently underway to establish the effects of DPP-4 inhibitors on major adverse cardiovascular events (MACE), but to-date no major clinical trial has published results. Using simulations, we evaluated the effectiveness of DPP-4 inhibitors in preventing MACE in two populations with type 2 diabetes, relative to the standard of care. METHODS: We used the Archimedes ARCHeS platform to simulate two clinical trials of virtual individuals with diagnosed type 2 diabetes (N=11,000 each).  The DPP-4 class was modeled with a meta-analysis of HbA1c and weight change, pooling results from published trials. The study treatments were added-on to standard care. The first simulated trial examined subjects with elevated cardiovascular (CV) risk, based on established CV disease or multiple risk factors. The second considered individuals on metformin monotherapy with HbA1c ≥ 7%.  We tracked changes in biomarkers and outcomes for 20 years. RESULTS: The DPP-4 class was associated with HbA1c drops of 0.66% [0.71% , 0.62% ] in the elevated CV risk population and 0.71% [0.75%,0.67%] in the metformin add-on population; and a weight drop of 0.14 [0.36,-0.07] kg in both cohorts.  The biomarker benefits produced a relative risk (RR) for MACE at 5 years of 0.977 [0.968, 0.986] and 0.962 [0.949, 0.975] for the elevated CV risk population and metformin add-on population, respectively.  The number needed to treat to prevent one occurrence of MACE at 5 years was 327 [233,550] in the elevated CV risk population.  CONCLUSIONS: Our simulated study suggests that DPP-4 inhibitors do not increase the risk of MACE relative to the standard of care in a population with elevated CV risk, and a representative diabetic metformin monotherapy population. This study provides insights on the long term benefits of DPP-4 inhibitors, and will support interpretation of the CV safety trial results likely to be published soon.